Anti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc.docVIP

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Anti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc.doc

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Anti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc

Anti-PrionDrugmPPIg5InhibitsPrPCConversiontoPrPSc JamesM.McCarthy1*,MarkusFranke2,UlrikeK.Resenberger3,SibealWaldron1,JeremyC.Simpson1, Jo¨rgTatzelt3,4,DietmarAppelhans2,MarkS.Rogers1 1SchoolofBiologyandEnvironmentalScience,UniversityCollegeDublin,Belfield,Dublin,Ireland,2LeibnizInstituteofPolymerResearchDresden,Dresden,Germany, 3Neurobiochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, Munich, Germany, 4German Center for Neurodegenerative Diseases (DZNE), Munich,Germany Abstract Priondiseases,alsoknownastransmissiblespongiformencephalopathies,areagroupoffatalneurodegenerativediseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans.The‘proteinonlyhypothesis’advocatesthatPrPSc,anabnormalisoformofthecellularproteinPrPC,isthemain and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminatePrPScincellculturemodels.Ofparticularinterestaresyntheticpolymersknownasdendrimerswhichpossessthe uniqueabilitytoeliminatePrPScinbothanintracellularandinvitrosetting.Theefficacyandmodeofactionofthenovel anti-priondendrimermPPIg5wasinvestigatedthroughthecreationofanumberofinnovativebio-assaysbaseduponthe scrapiecellassay.TheseassayswereusedtodemonstratethatmPPIg5isahighlyeffectiveanti-priondrugwhichacts,at leastinpart,throughtheinhibitionofPrPCtoPrPScconversion.Understandinghowadrugworksisavitalcomponentin maximisingitsperformance.ByestablishingtheefficacyandmethodofactionofmPPIg5,thisstudywillhelpdetermine whichdrugsaremostlikelytoenhancethiseffectandalsoaidthedesignofdendrimerswithanti-prioncapabilitiesforthe future. Citation:McCarthyJM,FrankeM,ResenbergerUK,WaldronS,SimpsonJC,etal.(2013)Anti-PrionDrugmPPIg5InhibitsPrPCConversiontoPrPSc.PLoSONE8(1): e55282.doi:10.1371/journal.pone.0055282 Editor:InaMaja